Eukaryotic mRNAs can initiate translation by either cap-dependent or cap-independent mechanisms. Presently, the relative contributions of these mechanisms to the proteome are unknown; however, some studies suggest that cap-independent mechanisms may account for the translation of many mRNAs. For some mRNAs, cap-independent translation is facilitated by sequence elements termed internal ribosome entry sites (IRESes). IRESes were first discovered in uncapped picornavirus RNAs and were subsequently identified in other viral and cellular mRNAs from mammals, insects, and yeast. For some mRNAs, IRESes facilitate translation when cap-dependent initiation is less efficient or blocked. Internal initiation also facilitates the translation of particular mRNAs with 5′ leaders that are encumbered by numerous upstream AUGs or RNA secondary structures.
A variety of evidence suggests that different IRESes vary in length, sequence composition, and in their requirements for initiation factors or other trans-acting factors, suggesting that internal initiation of translation occurs by a number of different mechanisms. Some IRESes are modular in composition. For example, an IRES module from the 5′ leader of the Gtx homeodomain mRNA showed that maximal activity was obtained with sequences of 7 nucleotides. Various lines of evidence suggested that the mechanism underlying the activity of this sequence element involves base pairing to a complementary sequence of 18S rRNA. In another study, a 22-nt IRES was identified in the 5′ leader of the Rbm3 mRNA. In addition, it has been reported that the 5′ leader of the thymidine kinase mRNA contains an IRES-element and that the 5′ leader of the c-myc mRNA contains two short IRES elements.
The short size of some IRES/TEE modules suggests that they may be prevalent within mRNA populations.
Some IRES elements can also function as translation enhancer elements (TEEs), i.e., they can enhance translation in the context of a monocistronic mRNA. However, not all TEEs are IRESes and not all IRESes are TEEs.